Project 2 The abnormal spine morphology found in disorders of memory and cognifion is suggestive of defects in the local cytoskeleton. Evidence that signaling pathways controlling the organizafion of actin networks are disturbed in several instances of retardation accords with this idea. The proposed work uses recent advances in immunofluorescence microscopy and image reconstitufion to test if activity-driven reorganization ofthe spine cytoskeleton is defective in rodent models of human conditions in which memory is impaired. A second group of studies will develop methods for reducing these defects, both in vitro and in vivo, and test if the treatments normalize long-term memory. The project involves four sets of experiments. Aim One will define signaling pathways used by three normally present factors [Brain-Derived Neurotrophic Factor (BDNF), adenosine, estrogen] to potently influence the assembly and stabilization of acfin filaments within spines following the induefion of long-term potenfiation (LTP). Each of these modulators has been implicated in the failure of LTP to consolidate (stabilize) in the animal models. Aim Two will use the results from Aim One to identify LTP-related defects in spine actin signaling in rodent models of menopause, middle-age, and eariy stage Huntington's Disease. Additional work addresses the prediction that BDNF will normalize acfin signaling in each of these cases. Aim Three will test if the spine signaling problems identified in Aim Two occur in the three groups of animals while they are learning a complex environment. Published work and preliminary results conflrm that LTP-related actin signaling is present in normal rats tested in this behavioral paradigm. Aim Four will determine if chronic up-regulation of BDNF producfion in the three rodent models normalizes actin signaling in vivo and if this is accompanied by improved memory scores. The proposed work will substanfially increase our understanding of how diverse memory disorders disrupt the final steps in consolidafing synapfic changes and memory, and rigorously test a mechanism-based, pharmacologically plausible strategy for correcfing such disrupfions. RELEVANCE (See instructions): Currenfiy no treatments exist for the memory impairments that afflict much of the populafion. The proposed work will test if diverse memory disorders develop from deficits in a final common pathway, and if each can be treated using a novel application of drugs already in clinical trials. The work thus has the potenfial of describing means for rapidly translafing growing knowledge ofthe neurobiological substrates of memory into plausible therapeufics for a major health problem.